PROJECT SUMMARY/ ABSTRACT Despite the implementation of surveillance programs for early diagnosis of hepatocelllular carcinoma (HCC), most patients are currently diagnosed at intermediate or advanced stage of the disease for which there are no curative interventions. These patients either receive transarterial chemoembolization or the molecular therapy, sorafenib. While these therapies have proven to prolong survival for some patients, many fail to receive any benefit due to treatment toxicities, poor liver function or drug resistance. The long term survival for HCC patients remains poor, with a 5-year survival rates <12%. Novel therapies against HCC are urgently needed as the incidence of HCC is steadily increasing in the United States. In recent years the natural omega-3 fatty acid, docosahexaenoic acid (DHA) has been shown to possess promising anticancer properties and its consumption has been implicated in reducing the risk of HCC. The effects of dietary DHA on established solid tumors is nominal. To address this issue, our lab has recently engineered a novel low-density lipoprotein (LDL) based nanoparticle that is reconstituted with unesterified DHA (herein referred to as LDL-DHA). Therapeutically, we have shown that the LDL-DHA nanoparticle is able to selectively kill rodent HCC cells at doses that do not harm primary hepatocytes. Furthermore, in a syngeneic rat model of HCC, locoregional delivery of LDL-DHA nanoparticles (achieved via surgical exposure and catheterization of the hepatic artery) is able to induce extensive necrosis (>80%) of HCC tumors and impede the tumor growth (3 fold) without injury to surrounding normal liver. This therapeutic selectivity is germane to HCC, as the background liver disease in intermediate and advanced HCC is often prone to treatment induced injury. The goal of the present proposal is to evaluate the utility image-guided minimally invasive locoregional LDL-DHA therapy for the management of HCC. To address this goal we will examine the following specific aims: 1) Optimize tumor targeting efficacy for catheter-based locoregional delivery of LDL nanoparticles to HCC under fluoroscopy guidance; 2) Investigate the efficacy of fluoroscopy-guided locoregional LDL-DHA treatment in inducing tumor necrosis in HCC; 3) Evaluate the role of amide proton transfer magnetic resonance imaging as a novel molecular imaging approach to quantitatively assess tumor response to LDL-DHA therapy. At the completion of this project, we expect that the combined work of these Aims will: (i) optimize the minimal invasive image-guided locoregional delivery of LDL-DHA nanoparticles to achieve maximum tumor uptake and tumor eradication; and (ii) to noninvasively quantify tumor response and forecast long term patient outcome following LDL-DHA treatment. The LDL-DHA treatment strategy will be significant because it offers a new method of treating HCC without secondary injury to the surrounding liver. Ultimately it is our endeavor to bring this technology to human patients, where it is anticipated to have an important impact on the current management of unresectable HCC by providing patients with a safe and viable approach to treating this aggressive cancer.